Studies in infectious disease and autoimmunity models have shown that immune responses to both self and foreign antigens are frequently dominated by induction of a particular Th1/Th2 subset with profound consequences for clinical outcome. Although the inflammatory effector function of Th1 cells is essential for the clearance of intracellular pathogens, it is also responsible for the tissue damage typical of organ-specific autoimmunity. Th2 cells which play an important role in the clearance of many helminthic infections function as suppressor cells or ineffectual bystanders in organ-specific autoimmune diseases. We have focused our efforts on identification of the cytokines that play critical roles in the induction of Th1 and Th2 responses. Myelin oligodendrocyte glycoprotein (MOG) is a minor oligodendrocyte specific protein that is incorporated into the outermost surface of the myelin sheath, but its function in the CNS is unknown. MOG-specific T and B cells play an important role both in multiple sclerosis (MS) in man and in experimental allergic encephalomyelitis (EAE) in animal models. Mice expressing a transgenic (Tg) TCR specific for an autoantigen have proven to be very useful in studying the pathogenesis of autoimmune disease. Because of the importance of MOG-specific T cells in the pathogenesis of MS and EAE, we have generated a TCR Tg mouse expressing TCR a- and b-chains derived from an encephalitogenic T cell clone specific for MOG35-55. We originally expected that this TCR Tg mouse (13A) would develop EAE spontaneously as the TCR genes were derived from a highly pathogenic T cell clone that readily induced EAE upon transfer to normal un-manipulated recipients. However, the phenotype of a clone may bear no relationship to the phenotype of a transgenic mouse expressing the TCR genes derived from that clone. Indeed, the 13A line fails to develop EAE spontaneously and differs from several other TCR Tg lines specific for MBP as it also fails to develop EAE in the absence of regulatory T cells when crossed to RAG deficient mice that lack T or B lymphocytes. Resistance to disease was not absolute as mild EAE at delayed onset developed after immunization of 13A mice with MOG in CFA and following transfer of 13A Th1 cells to RAG -/- recipients or immunization of the TCR Tg RAG -/- mice with MOG in CFA. Detailed analysis of the function of the TCR Tg T cells demonstrated an unusual and previously undescribed phenotype. The TCR Tg T cells produced large amounts of IL-4 when stimulated in vitro with MOG35-55 and underwent FAS/FAS-L-mediated activation induced cell death (AICD) when stimulated with MOG35-55 in the presence of IL-12. This phenotype was acquired in the periphery and not during T cell differentiation in the thymus. Although the phenotype of the MOG-specific T cells in the 13A mice has not previously been described in other autoantigen-specific TCR Tg mice, almost all of their TCRs recognize antigens that are expressed in the thymus and/or in the periphery. Thus, the 13A phenotype may be typical of autoantigen-specific T cells that completely escape deletion in the thymus. As MOG represents an important target antigen in MS in man and has been definitively been shown to be only expressed in the CNS, a careful search for IL-4 producing, AICD-susceptible MOG-specific T cells in MS patients may be of interest. More importantly, an approach to enhancing the numbers and function of these unique cells might be of therapeutic benefit. Activation of T cells during an immune response requires two signals. Signal one is delivered through the binding of the TCR to the antigen-MHC complex, while signal two is delivered by co-stimulatory molecules on APC. The best-characterized co-stimulatory molecules on APCs are CD80 and CD86, which bind CD28 on T cells. Many members of the tumor necrosis factor receptor (TNFR)-TNF super-family also exhibit co-stimulatory function. The most highly studied is OX40 (CD134) and its ligand, the OX40L (CD134L). OX40/OX40L interactions have been shown to exert potent co-stimulatory effects on T cell activation. OX40 expression is transiently upregulated on T cells following TCR engagement, while OX40L is expressed on APC following activation. Although the OX40L has been reported to be expressed by T cells, the requirements for induction of OX40L on T cells have not been studied in detail. During the course of our studies on the 13A mouse, we demonstrated that the OX40L can be induced on murine CD4+ and CD8+ T cells after 6 days of culture under Th1, but not Th2, conditions. Induction of OX40L expression required a high concentration of IL-12, was not seen in the presence of IFN-g, but in the absence of IL-12, and was STAT4-dependent. Notably, induction of OX40L on T cells was only seen at very low concentrations of antigen or anti-CD3. T cell-expressed OX40L was fully capable of delivering a potent co-stimulatory signal that enhanced the proliferation of CD4+ T cells as well as promoted their differentiation to Th2 cells. OX40L expression could also be induced on CD4+ T cells in vivo following immunization with low dose antigen and an IL-12 inducer. OX40/OX40L interactions between antigen-specific T cells may occur in T cell zones in lymph node and spleen when OX40L expression has diminished on APC. Co-stimulation by T cell expressed OX40L may result in deviation of a Th1 response to a Th2 response under conditions where T cells are exposed to low concentrations of foreign or autoantigens in the presence of high concentrations of IL-12.